Stereoselective allyl amine synthesis through enantioselective addition of diethylzinc and [1,3]-chirality transfer: Synthesis of lentiginosine and polyoxamic acid derivative

Article abstract of DOI:10.1002/chem.200400830

A new synthetic method for the preparation of allyl amines has been developed. The key steps of this method are enantioselective addition of diethylzinc and [1,3]-chirality transfer through the [3.3] sigmatropic rearrangement of allyl cyanates. Stereocont

Full text of DOI:10.1002/chem.200400830

FULL PAPER
Stereoselective Allyl Amine Synthesis through Enantioselective Addition of
Diethylzinc and [1,3]-Chirality Transfer: Synthesis of Lentiginosine and
Polyoxamic Acid Derivative
Yoshiyasu Ichikawa,*[a] Takashi Ito,[b] and Minoru Isobe[b]
Abstract: A new synthetic method for the preparation of allyl amines has been de-
veloped. The key steps of this method are enantioselective addition of diethylzinc
Keywords: asymmetric synthesis ·
and [1,3]-chirality transfer through the [3.3] sigmatropic rearrangement of allyl cy-
natural products · rearrangement ·
anates. Stereocontrolled syntheses of lentiginosine (1) and polyoxamic acid deriva-
synthesis design · total synthesis
tive 2 from a common intermediate 7 derived from d-tartaric acid (8), have been
accomplished.
Introduction
As part of our research program aimed at the development
of [3.3] sigmatropic rearrangements of allyl cyanates for the
synthesis of natural products,[1] we recently proposed an ap-
proach for stereoselective allyl amine synthesis as shown in
Figure 1.[2] An enantioselective addition of diethylzinc
(Et2Zn) to a,b-unsaturated aldehyde A would furnish allyl
alcohol B with predictable stereoselectivity. This allyl alco-
hol B would then be transformed into allyl cyanate C, which
would undergo a concerted [3.3] bond reorganization to
afford allyl isocyanate D with a high degree of [1,3]-chirality
transfer.[3] Treatment of the resultant allyl isocyanate D with
alcohol would provide the corresponding carbamate E. It
should be noted that it is possible to chose the most appro-
priate carbamate as a protecting group for allyl amine.[4]
Further manipulation—ring-closing methathesis (RCM) of
F, for example—would offer the nitrogen-containing hetero-
Figure 1. A plan for stereoselective allyl amine synthesis.
cycle G, whereas oxidative cleavage of the double bond in E
could furnish the nonproteinogenic amino acid H.
In this synthetic protocol, when the R1 group in A has
stereogenic centers, a matched-mismatched problem might
be expected to arise during the synthesis of the allyl alcohol
(A!B).[5] In fact, it is well known that the stereochemical
outcome of asymmetric synthesis will often be to some
extent dependent on the relationship between the absolute
configuration of the chiral ligand and that of the substrate.
We envisioned that such a problem could be circumvented
in our case, because enantioselective addition of Et2Zn
would be carried out at the remote position, where the
effect of the R1 group should become negligible. Moreover,
since the transfer of chirality through allyl cyanate-to-isocya-
nate rearrangement (C!D) is quite reliable, due to its con-
certed six-membered transition state, we might accomplish
[a] Prof. Dr. Y. Ichikawa
Faculty of Science, Kochi University
Akebono-cho, Kochi 780–8520 (Japan)
Fax : (+81)88-844-8359
E-mail: ichikawa@cc.kochi-u.ac.jp
[b] T. Ito, Prof. Dr. M. Isobe
Laboratory of Organic Chemistry, School of Bioagricultural Sciences
Nagoya University, Chikusa, Nagoya 464–8601 (Japan)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2005, 11, 1949 – 1957
DOI: 10.1002/chem.200400830
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1949

the construction of a stereogenic center bearing an N-sub-
stituent in proximity to the R1 group.
To demonstrate the efficiency of this stereoselective allyl
amine synthesis, we planned to synthesize lentiginosine (1)
and the polyoxamic acid derivative 2 (Figure 2). Lentigino-
Figure 3. Retrosynthetic analysis of 1 with a common intermediate.
diphenyl(1-methylpyrrolidin-2-yl)methanol (DPMPM), first
reported by Soai,[11] and the results are depicted in Figure 4.
Treatment of the aldehyde 9[12] with Et2Zn in the presence
Figure 2. Two target molecules: lentiginosine (1) and the polyoxamic acid
derivative 2.
sine was isolated in 1990 from the leaves of Austragalus len-
tiginosus, and this dihydroxylated indolizine alkaloid is a
strong inhibitor of the fungal a-glucosidase amyloglucosi-
dase, an enzyme that hydrolyzes 1,4- and 1,6-a-glucosidic
linkages.[6] Polyoxamic acid (3) is known to be a structural
constituent of polyoxins,[7] a class of peptidyl-nucleoside an-
tifungal antibiotics.[8] This unusual amino acid has three con-
tiguous stereocenters, and the polyoxamic acid derivative 2
is an intermediate for the synthesis of polyoxin J (4).[9] Here
we describe syntheses of lentiginosine (1) and the polyoxa-
mic acid derivative 2 by the stereoselective allyl amine syn-
thesis represented in Figure 1.
Results and Discussion
Synthetic plan: Our synthetic analysis demonstrating how
the two target molecules, lentiginosine (1) and the polyox-
amic acid derivative 2, could be prepared from a common
intermediate 7 derived from d-tartaric acid (8) is shown in
Figure 3.[10] It should be noted that the stereogenic center of
the nitrogen-bearing carbon in the intermediate 5 for lenti-
ginosine is the opposite of that in 6 for the polyoxamic acid
derivative 2. Consequently, this synthetic plan offers an ap-
propriate situation to test our expectation that the nitrogen-
bearing stereocenter could be constructed diastereoselec-
tively at the position adjacent to the other stereogenic cen-
ters.
Figure 4. Enantioselective addition of Et2Zn to aldehyde 9.
of a catalytic amount of (R)-DPMPM (6 mol%) in cyclo-
hexane at 08C for 7 h provided the allyl alcohol 10 in 91%
yield with a high 93:7 diastereoselectivity (entry A, deter-
1
mined by H NMR).
The structure for 10 was initially assigned by the Soai em-
pirical rule and finally confirmed by Mosher–Kusumi MTPA
ester analysis, which has been widely used to determine the
absolute configurations of secondary alcohols (Figure 5).[13]
Thus, the secondary alcohol 10 was transformed into the cor-
responding (S)- and (R)-MTPA esters 12, and their chemical
shift differences (Dd values: Dd = dSꢀdR) were calculat-
ed.[13] The protons with positive Dd values are placed on the
right side in the configurational correlation model and those
Stereoselective synthesis of allyl amine intermediates: Our
initial efforts focused on the enantioselective addition of
Et2Zn to the a,b-unsaturated aldehyde 9 in the presence of
1950
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Chem. Eur. J. 2005, 11, 1949 – 1957

Stereoselective Allyl Amine Synthesis
FULL PAPER
Scheme 1. Synthesis of allyl amine intermediate 16 for lentiginosine.
workup and chromatographic purification in a good 82%
yield from allyl alcohol 10.
The stereochemical outcome of this [1,3]-chirality transfer
process was determined by the Kusumi MTPA-amide
method (Figure 6).[15] Thus, the Troc-carbamate 16 was
Figure 5. Mosher–Kusumi MTPA ester analysis: configurational correla-
tion model and Dd values for the Mosher ester derivative 12 (Dd =
dSꢀdR).
with negative Dd on the left side. This procedure elucidated
the absolute stereochemistry of secondary alcohol 10 as the
S configuration.
With 6 mol% of (S)-DPMPM as catalyst, enantioselective
addition of Et2Zn to aldehyde 9 proceeded smoothly with
good face selectivity to furnish predominantly the product
11 (93:7, 1H NMR) in 87% yield (entry B; see Figure 4).
Since the yields and selectivities in entries A and B are com-
parable, it is evident that the stereochemical outcome of this
Soai protocol is independent of the relationship between the
Figure 6. Kusumi MTPA amide analysis of 17.
respective absolute configurations of aldehyde
9 and
DPMPM and that reagent control is dominant in this reac-
tion.
transformed into the corresponding (S)- and (R)-MTPA
amides 17, and analysis of their Dd values in terms of the
configurational correlation model depicted in Figure 5 con-
firmed the asymmetric carbon bearing the nitrogen substitu-
ent to have the S configuration. Figure 7 shows the cyclic
transition state through which the allyl cyanate-to-isocya-
nate rearrangement may pass. The stereochemistry of the
newly formed stereogenic center in 15 is consistent with the
concerted six-membered cyclic transition state B!C in
Having obtained two allyl alcohols, we next turned our at-
tention to the preparation of allyl amine intermediates by
way of the allyl cyanate-to-isocyanate rearrangement
(Scheme 1). Treatment of allyl alcohol 10[14] with trichloro-
acetyl isocyanate, followed by hydrolysis with potassium car-
bonate in aqueous methanol, gave the carbamate 13. Dehy-
dration of 13 with triphenylphosphine, carbon tetrabromide,
and triethylamine at ꢀ208C gave the allyl cyanate 14, which
underwent a [3.3] sigmatropic
rearrangement to afford the
allyl isocyanate 15. Since isola-
tion of 15 by aqueous workup is
difficult, due to the hydrolysis
of the isocyanate group, the re-
action mixture was treated in
situ with 2,2,2-trichloroethanol.
The trichloroethoxy (Troc) car-
Figure 7. The cyclic six-membered transition state C through which the allyl cyanate-to-isocyanate rearrange-
bamate 16 was isolated after ment A!D may pass.
Chem. Eur. J. 2005, 11, 1949 – 1957
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Y. Ichikawa et al.
which the ethyl group adopts a pseudoequatorial orienta-
tion.[16]
For the synthesis of the polyoxamic acid derivative, it was
necessary to prepare the diastereomer of 16, namely 18,
which was also accomplished by a procedure similar to that
shown in Scheme 1. Accordingly, [1,3]-chirality transfer in
allyl alcohol 11 was achieved through the [3.3] sigmatropic
rearrangement of the allyl cyanate to afford ally carbamate
18 in 83% overall yield (Scheme 2).
Scheme 4. Synthesis of the nosyl intermediate 22 and its cyclization by
RCM to give 23.
amine with o-nitrobenzenesulfonyl chloride and triethyl-
amine. Fortunately, diastereomerically pure 21 was obtained
in 86% yield after recrystallization from a mixture of
AcOEt and hexane, and the minor isomer could readily be
removed at this stage. Following the Fukuyama method for
the synthesis of secondary amines,[18] the o-nosyl amide 21
was treated with 3-buten-1-ol under Mitsunobu conditions
(PPh3, DEAD, benzene) to furnish the 1,7-diene 22 in 89%
yield. A ruthenium-catalyzed RCM of 22 in the presence of
Grubbs I catalysis (7 mol%) in benzene at 608C for 90 min
successfully constructed the tetrahydropyridine ring to
afford the cyclized product 23 in good yield (92%). The
higher yield in this RCM reaction relative to that shown in
Scheme 3 may be explained by the buttressing effect of the
o-nitrobenzenesulfonyl group.[19]
Scheme 2. Preparation of the allyl amine intermediate 18 for the poly-
oxamic acid derivative.
Synthesis of lentiginosine: Having established an efficient
route for the preparation of allyl amine intermediate 16,
which possesses the three stereogenic centers necessary for
lentiginosine synthesis, we next turned to the construction of
the lactam ring through RCM (Scheme 3). Deprotection of
The next task was the preparation of the dihydroxylated
five-membered ring of the lentiginosine framework
(Scheme 5). Removal of the silyl protecting group in 23 with
Scheme 3. Synthesis of the unsaturated lactam 20 by RCM.
16 with zinc and acetic acid in THF, followed by treatment
of the resulting amine with but-3-enoyl chloride, furnished
amide 19 as an oil. A ruthenium-catalyzed RCM in the pres-
ence of 10 mol% of Grubbsꢁ catalysis (Grubbs I; benzyl-
idene-bis(tricyclohexylphosphine)dichlororuthenium)[17] in
benzene at 608C afforded the unsaturated lactam 20 in 73%
yield.
At this stage we felt it was unfortunate that there had
been no opportunity to separate the minor isomer arising
from enantioselective addition of Et2Zn over the steps from
allyl alcohol 10. To solve this problem, we elected to pre-
pare the o-nitrobenzenesulfonamide derivative, in view of
the pronounced tendency of such derivatives to crystallize
(Scheme 4). Thus, the o-nosyl amide 21 was prepared by de-
protection of 16 and subsequent treatment of the resultant
Scheme 5. Synthesis of lentiginosine (1).
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Chem. Eur. J. 2005, 11, 1949 – 1957

Stereoselective Allyl Amine Synthesis
FULL PAPER
tetra-n-butylammonium fluoride, followed by tosylation of
the resulting primary alcohol 24, furnished the tosylate 25 in
83% yield over two steps. Since removal of the o-nosyl
group in 25 gave no cyclized product,[20] the acetonide group
used for diol protection in 25 was transformed into a bis-
(methoxymethyl) (MOM) system by acid-catalyzed hydroly-
sis of the acetonide group with HCl (3n) in aqueous THF,
followed by MOM protection of the resulting diol with di-
methoxymethane in the presence of phosphorous pentox-
ide[21] to afford 26 in 74% yield over the two steps. Removal
of the o-nosyl group (26!27) with concomitant construction
of a pyrrolidine ring (27!28) was achieved by treatment of
26 with thiophenol and cesium carbonate in acetonitrile,
giving the cyclized product 28 in 85% yield. Catalytic hydro-
genation of alkene 28 with platinum in ethanol afforded the
indolizine 29 in 85% yield. Finally, removal of the two
MOM groups in 29 with HCl (3n) in hot aqueous MeOH
(558C), followed by treatment with ion-exchange resin (Am-
berlite IRA 410), furnished an 82% yield of lentiginosine
Conclusion
We have established a highly efficient synthetic method for
allyl amines by a sequence of steps involving enantioselec-
tive addition of Et2Zn and [3.3] sigmatropic rearrangement
of allyl cyanates. As demonstrated in the synthesis of lentigi-
nosine (1) and the polyoxamic acid 2, the asymmetric center
bearing the nitrogen substituent could be constructed with-
out the problems of substrate/reagent matching and mis-
matching. Further applications of this method to the synthe-
sis of natural products are under investigation in our group.
Experimental Section
Melting points were recorded on a micro melting point apparatus and
are not corrected. Optical rotations are given in units of 10ꢀ1degcm2 gꢀ1
.
Infrared spectra are reported as wavenumbers (cmꢀ1). 1H NMR data are
reported as follows: chemical shift (d), integration, multiplicity (s = sin-
glet, d = doublet, t = triplet, q = quartet, br = broadened, m = mul-
tiplet), coupling constants (J, given in Hz). 13C NMR chemical shifts (d)
are recorded in parts per million (ppm) relative to CDCl3 (d = 77.0),
CD3OD (d = 49.0), or tBuOH (d = 30.29, in D2O) as internal standards.
High-resolution mass spectra (HRMS) are reported in m/z. Reactions
were run under nitrogen when sensitive to moisture or oxygen. Dichloro-
methane was dried over molecular sieves (3 ꢂ). Pyridine and triethyl-
amine were stocked over anhydrous KOH. All other commercially avail-
able reagents were used as received.
1
(1), the H and 13C NMR spectroscopic properties of which
were in good agreement with those previously reported by
Greene.[6l]
Synthesis of polyoxamic acid: The synthesis of the polyox-
amic acid derivative 2 started with removal of the Troc
group in 18 with zinc and acetic acid in THF (Scheme 6).
(2E,4S,5S)-6-[(tert-Butyldimethylsilyl)oxy]-4,5-(isopropylidenedioxy)hex-
2-enal (9): IBX (o-iodoxybenzoic acid, 250 mg) was added portionwise at
08C to a solution of allyl alcohol 7 (208 mg, 0.69 mmol) in DMSO
(7.0 mL). After stirring at room temperature for 4 h, the reaction mixture
was diluted with hexane and ether. The resulting suspension was poured
into ice-cooled water and then filtered through a pad of Hyflo Super
Cell. The separated aqueous layer was extracted with Et2O, and the com-
bined organic layer was washed with brine, dried over anhydrous
Na2SO4, and then concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography (AcOEt/hexane 1:30)
to afford aldehyde 9 (187 mg, 90%) as a colorless oil : [a]2D8 ꢀ3.2 (c =
1.10, CHCl3); 1H NMR (CDCl3, 400 MHz): d = 0.08 (s, 3H), 0.09 (s,
3H), 0.91 (s, 9H), 1.43 (s, 3H), 1.45 (s, 3H), 3.72–3.90 (m, 3H), 4.63
(ddd, J = 8, 5, 1.5 Hz, 1H), 6.39 (ddd, J = 15.5, 8, 1.5 Hz, 1H), 6.83 (dd,
J = 15.5, 5 Hz, 1H), 9.59 ppm (d, J = 8 Hz, 1H); 13C NMR (CDCl3,
100 MHz): d = ꢀ5.5, ꢀ5.4, 18.3, 25.8, 26.7, 26.9, 63.0, 78.1, 80.7, 110.2,
131.9, 153.3, 193.1 ppm; IR (KBr): n˜ = 2932, 1699, 1096 cmꢀ1; elemental
analysis calcd (%) for C15H28O4Si: C 59.96, H 9.39; found: C 59.93, H
9.26.
Scheme 6. Synthesis of the polyoxamic acid derivative 2.
(3S,4E,6S,7S)-8-[(tert-Butyldimethylsilyl)oxy]-6,7-(isopropylidenedioxy)-
oct-4-en-3-ol (10): A solution of (S)-(+)-DPMPM (122 mg, 0.46 mmol)
and aldehyde 9 (2.30 g, 7.65 mmol) dissolved in cyclohexane (26.0 mL)
was heated at reflux for 30 min under nitrogen atmosphere, and was then
cooled to 08C. Diethylzinc (1.02m solution in hexane, 16.5 mL,
16.8 mmol) was added, and the mixture was stirred at 08C for 7 h. The
reaction mixture was diluted with Et2O and then poured into aqueous
KHSO4 solution (1m), and the separated aqueous layer was extracted
with Et2O. The combined organic layer was washed with water, saturated
aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, and then
concentrated under reduced pressure. The resulting residue was purified
by silica gel chromatography (AcOEt/hexane 1:20) to afford allyl alcohol
10 (2.31 g, 91%) as a colorless oil: [a]2D7 +1.71 (c = 0.99, CHCl3); 1H
NMR (CDCl3, 400 MHz): d = 0.07 (s, 3H), 0.08 (s, 3H), 0.90 (s, 9H),
0.94 (t, J = 7 Hz, 3H), 1.41 (s, 3H), 1.42 (s, 3H), 1.52–1.61 (m, 2H),
3.68–3.81 (m, 3H), 4.02–4.12 (m, 1H), 4.36 (t, J = 7 Hz, 1H), 5.72 (ddd,
J = 15.5, 7, 1 Hz, 1H), 5.84 ppm (dd, J = 15.5, 6 Hz, 1H); 13C NMR
(CDCl3, 100 MHz): d = ꢀ5.5, ꢀ5.3, 9.6, 18.3, 25.9, 26.9, 27.1, 29.9, 62.4,
Reprotection of the resulting amine with di-tert-butyl dicar-
bonate and triethylamine provided the Boc-carbamate 30 in
88% yield. Oxidative cleavage of the double bond in 30 was
carried out by ozonolysis, and the aldehyde produced was
immediately subjected to sodium chlorite oxidation to fur-
nish the protected polyoxamic acid 31 in 85% yield (two
steps). Treatment of this acid 31 with diazomethane in meth-
anol provided the methyl ester 32 in 97% yield. Removal of
the silyl group in 32 by Ghoshꢁs procedure with tetrabuty-
lammonium fluoride and carbamoylation of 33 by treatment
with trichloroacetyl isocyanate and aluminium oxide[22] fur-
nished the Boc-protected carbamoylpolyoxamic acid ester 2
in 86% yield.
Chem. Eur. J. 2005, 11, 1949 – 1957
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Y. Ichikawa et al.
73.2, 78.3, 81.5, 109.0, 127.9, 136.8 ppm; IR (KBr): n˜ = 3431, 2959, 2932,
1254, 1092 cmꢀ1
aqueous KHSO4 (1m), water, saturated aqueous NaHCO3, and brine, and
dried over anhydrous Na2SO4. Concentration under reduced pressure
provided the residue, which was purified by silica gel chromatography
(AcOEt/hexane 1:5) to afford allyl carbamate (147 mg, 97%) as a color-
less oil.
.
(3R,4E,6S,7S)-8-[(tert-Butyldimethylsilyl)oxy]-6,7-(isopropylidenedioxy)-
oct-4-en-3-ol (11): A solution of (R)-(ꢀ)-DPMPM (83 mg, 0.31 mmol)
and aldehyde 9 (1.56 g, 5.19 mmol) dissolved in cyclohexane (18.0 mL)
was heated at reflux for 30 min under nitrogen, and was then cooled to
08C. Diethylzinc (1.02m solution in hexane, 11.2 mL, 11.42 mmol) was
added dropwise, and the solution was stirred at 08C for 4 h. The reaction
mixture was diluted with Et2O and poured into aqueous KHSO4 solution
(1m). The separated aqueous layer was extracted with Et2O, and the
combined organic layer was washed with water, saturated aqueous
NaHCO3, and brine, dried over anhydrous Na2SO4, and then concentrat-
ed under reduced pressure. The resulting residue was purified by silica
gel chromatography (AcOEt/hexane 1:20) to afford allyl alcohol 11
(1.50 g, 87%) as a colorless oil: [a]2D4 ꢀ10.7 (c = 0.45, CHCl3); 1H NMR
(CDCl3, 400 MHz): d = 0.06 (s, 3H), 0.07 (s, 3H), 0.90 (s, 9H), 0.93 (t, J
= 7.5 Hz, 3H), 1.41 (s, 3H), 1.43 (s, 3H), 1.50–1.63 (m, 2H), 3.68–3.80
(m, 3H), 4.06 (q, J = 6.0 Hz, 1H), 4.36 (t, J = 7.0 Hz, 1H), 5.70 (ddd, J
= 15.5, 7.0, 1.0 Hz, 1H), 5.83 ppm (ddd, J = 15.5, 6.0, 0.5 Hz, 1H); 13C
NMR (100 MHz): d = ꢀ5.5, ꢀ5.3, 9.7, 18.3, 25.9, 26.9, 27.1, 29.9, 62.4,
Carbon tetrabromide (502 mg, 1.51 mmol) in CH2Cl2 (2.0 mL) was added
at ꢀ108C under nitrogen to a solution of the allyl carbamate (147 mg,
0.39 mmol), triphenylphosphine (356 mg, 1.36 mmol), and triethylamine
(352 mL, 2.52 mmol) in CH2Cl2 (5.0 mL). The reaction mixture was stirred
at ꢀ108C for 20 min, and was then treated with 2,2,2-trichloroethanol
(1.50 mL, 15.6 mmol). After the solution had been allowed to warm to
room temperature, the stirring was continued for 8 h. The mixture was di-
luted with Et2O and aqueous KHSO4 (1m), and the separated aqueous
layer was extracted with Et2O. The combined organic layer was washed
with water, saturated aqueous NaHCO3, and brine, and was dried over
anhydrous Na2SO4. Concentration under reduced pressure afforded the
residue which was purified by silica gel chromatography (AcOEt/hexane
1:20) to afford Troc-carbamate 18 (168 mg, 86%) as a colorless oil: [a]D22
+2.9 (c = 1.51, CHCl3); 1H NMR (CDCl3, 400 MHz): d = 0.10 (s, 6H),
0.91 (s, 9H), 0.99 (t, J = 7.5 Hz, 3H), 1.38 (s, 3H), 1.42 (s, 3H), 2.03–
2.13 (m, 2H), 3.69 (dd, J = 11.5, 7.0 Hz, 1H), 3.78–3.90 (m, 1H), 3.84
(dd, J = 11.5, 7.5 Hz, 1H), 4.01 (dd, J = 7.5, 2.5 Hz, 1H), 4.38–4.45 (m,
1H), 4.72 (d, J = 11.5 Hz, 1H), 4.76 (d, J = 11.5 Hz, 1H), 5.48 (ddt, J =
15.5, 6.0, 1.5 Hz, 1H), 5.71 (brd, J = 9.0 Hz, 1H), 5.75 ppm (dtd, J =
15.5, 6.5, 1.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz): d = ꢀ5.4, 13.3, 18.4,
25.3, 25.3, 25.9, 26.9, 27.0, 52.5, 63.5, 74.5, 81.0, 95.7, 109.1, 125.6, 134.8,
73.5, 78.3, 81.5, 109.1, 128.1, 136.9 ppm; IR (KBr): n˜
1252 cmꢀ1
(3E,5S,6S,7S)-8-[(tert-Butyldimethylsilyl)oxy]-6,7-(isopropylidenedioxy)-
5-[(2,2,2-trichloroethoxycarbonyl)amino]-oct-3-ene (16): Trichloro-
= 3409, 2931,
.
acetyl isocyanate (650 mL, 5.46 mmol) was added at 08C to a solution of
the allyl alcohol 10 (903 mg, 2.73 mmol) in CH2Cl2 (12.0 mL). After stir-
ring at 08C for 20 min, the reaction mixture was concentrated under re-
duced pressure, and the resulting residue was dissolved in MeOH
(7.0 mL). Water (11.0 mL) and potassium carbonate (2.26 g, 16.4 mmol)
were added to the reaction mixture at 08C, and the cooling bath was re-
moved. After the mixture had been stirred at room temperature for 7 h,
the separated aqueous layer was extracted with CH2Cl2. The combined
organic layer was washed with aqueous KHSO4 (1m), water, saturated
aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, and then
concentrated under reduced pressure. The resulting residue was purified
by silica gel chromatography (AcOEt/hexane 1:4) to afford allyl carba-
mate 13 (972 mg, 95%) as a colorless oil.
154.2 ppm; IR (KBr): n˜ = 3337, 2932, 1748, 1508, 1252, 1081 cmꢀ1
.
(3E,5S,6S,7S)-8-[(tert-Butyldimethylsilyl)oxy]-6,7-(isopropylidenedioxy)-
5-[(2-nitrobenzenesulfonyl)amino]-oct-3-ene (21): Zinc powder (750 mg,
11.4 mmol) was added at room temperature to a solution of Troc-carba-
mate 16 (340 mg, 0.67 mmol) and AcOH (270 mL, 4.7 mmol) in THF
(17.0 mL). After vigorous stirring for 4 h, the resulting suspension was di-
luted with AcOEt, and filtered through a pad of Hyflo Super Cellꢃ . The
filtrate was concentrated, and the resulting residue was dissolved in
CH2Cl2. This solution was washed with saturated aqueous NaHCO3,
water, and brine, dried over anhydrous Na2SO4, and then concentrated
under reduced pressure. The resulting crude amine was dissolved in
CH2Cl2 (18.0 mL), and saturated aqueous NaHCO3 (17.0 mL) and 2-ni-
trobenzenesulfonyl chloride (450 mg, 2.02 mmol) were added at 08C.
After vigorous stirring at 08C for 2 h, the organic layer was separated
and the aqueous layer was extracted with AcOEt. N,N-Dimethyl-1,3-pro-
panediamine (0.19 mL, 1.51 mmol) was added at 08C to the combined or-
ganic layer to quench excess 2-nitrobenzenesulfonyl chloride. The so-
lution was washed with water and brine, dried over anhydrous Na2SO4,
and then concentrated to give a residue, which was purified by recrystalli-
zation (AcOEt and hexane) to afford o-nosylamide 21 (285 mg, 86%) as
Carbon tetrabromide (316 mg, 0.95 mmol) in CH2Cl2 (2.0 mL) was added
at ꢀ208C under nitrogen to the allyl carbamate 13 (91 mg, 0.24 mmol),
triphenylphosphine (223 mg, 0.85 mmol), and triethylamine (185 mL,
1.32 mmol) in CH2Cl2 (3.0 mL). The reaction mixture was allowed to
warm to 08C over 20 min and was then treated with 2,2,2-trichloroetha-
nol (260 mL, 2.68 mmol). After the mixture had been stirred at 08C for
1 h, the cooling bath was removed. After the mixture had then been stir-
red at room temperature for 2 h, ether and aqueous KHSO4 (1m) were
added, and the separated aqueous layer was extracted with Et2O. The
combined organic layer was washed with water, saturated aqueous
NaHCO3, and brine, dried over anhydrous Na2SO4, and then concentrat-
ed under reduced pressure. The resulting residue was purified by silica
gel chromatography (AcOEt/hexane 1:20) to afford Troc-carbamate 16
colorless needles: mp 67–688C; [a]2D8 +114.2 (c
=
1.50, CHCl3); 1H
NMR (CDCl3, 400 MHz): d = 0.08 (s, 3H), 0.09 (s, 3H), 0.71 (t, J =
7.5 Hz, 3H), 0.92 (s, 9H), 1.32 (s, 3H), 1.34 (s, 3H), 1.72–1.84 (m, 2H),
3.65–3.83 (m, 3H), 4.05 (dd, J = 7.5, 3.5 Hz, 1H), 4.12 (td, J = 9.0,
3.5 Hz, 1H), 5.22 (ddt, J = 15.5, 9.0, 1.5 Hz, 1H), 5.48 (dt, J = 15.5,
6.0 Hz, 1H), 5.82 (d, J = 9.0 Hz, 1H), 7.65–8.08 ppm (m, 4H); 13C NMR
(CDCl3, 100 MHz): d = ꢀ5.5, ꢀ5.4, 12.8, 18.3, 24.9, 25.9, 26.8, 26.9, 58.5,
63.8, 77.5, 81.0, 109.4, 123.0, 125.2, 131.3, 132.5, 133.1, 135.5, 138.2,
(106 mg, 86%) as a colorless oil: [a]2D8 ꢀ12.2 (c
=
1.17, CHCl3); 1H
NMR (CDCl3, 400 MHz): d = 0.08 (s, 6H), 0.91 (s, 9H), 1.00 (t, J =
7.5 Hz, 3H), 1.39 (s, 6H), 2.08 (dq, J = 7.5, 6.5 Hz, 2H), 3.68 (dd, J =
10, 6 Hz, 1H), 3.80 (dd, J = 10, 4.5 Hz, 1H), 3.84–3.91 (m, 1H), 4.02 (dd,
J = 7.5, 4 Hz, 1H), 4.24–4.31 (m, 1H), 4.72 (2H, s), 5.43 (brd, J =
7.5 Hz, 1H), 5.49 (dd, J = 15.5, 7.5 Hz, 1H), 5.78 ppm (dt, J = 15.5,
6.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz): d = ꢀ5.4, 13.3, 18.4, 25.3,
25.9, 26.9, 27.1, 54.9, 63.9, 74.6, 78.0, 80.7, 95.6, 109.5, 123.9, 137.0,
147.8 ppm; IR (KBr): n˜ = 3363, 2933, 1542, 1363, 1172, 1084, 743 cmꢀ1
;
elemental analysis calcd (%) for C23H38N2O7SSi: C 53.67, H 7.44, N 5.44;
found: C 53.69, H 7.49, N 5.36.
(3E,5S,6S,7S)-8-[(tert-Butyldimethylsilyl)oxy]-6,7-(isopropylidenedioxy)-
5-[(2-nitrobenzenesulfonyl)(pent-3-enyl)amino]-oct-3-ene (22): Diethyl
azodicarboxylate (40% toluene solution, 1.40 mL, 0.36 mmol) was added
153.8 ppm; IR (KBr): n˜ = 3321, 2933, 1745, 1509, 1252, 1092 cmꢀ1
.
(3R,4E,6S,7S)-3-[(Aminocarbonyl)oxy]-8-[(tert-butyldimethylsilyl)oxy]-
6,7-(isopropylidenedioxy)-oct-4-ene (18): Trichloroacetyl isocyanate
(96 mL, 0.80 mmol) was added at 08C to a solution of the allyl alcohol 11
(133 mg, 0.40 mmol) in CH2Cl2 (7.0 mL). After stirring at 08C for 20 min,
the solution was concentrated under reduced pressure, and the resulting
residue was dissolved in MeOH (3.0 mL). Water (3.0 mL) and potassium
carbonate (388 mg, 2.8 mmol) were added at 08C, and the stirring was
continued at room temperature for 6 h. The separated aqueous layer was
extracted with Et2O, and the combined organic layer was washed with
dropwise at 08C to
a solution of the o-nosylamide 21 (372 mg,
0.72 mmol), but-3-en-1-ol (217 mL, 2.53 mmol), and triphenylphosphine
(950 mg, 3.61 mmol) in benzene. After having been stirred at room tem-
perature for 7 h, the resulting mixture was concentrated under reduced
pressure to afford the residue, which was purified by silica gel chroma-
tography (AcOEt/hexane 1:7) to furnish the alkene 22 (367 mg, 89%) as
a
colorless oil: [a]2D7 +20.7 (c
=
2.92, CHCl3); 1H NMR (CDCl3,
400 MHz): d = 0.09 (s, 3H), 0.09 (s, 3H), 0.90 (s, 9H), 0.90 (t, J =
1954
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 1949 – 1957

Stereoselective Allyl Amine Synthesis
FULL PAPER
7.0 Hz, 3H), 1.36 (s, 3H), 1.37 (s, 3H), 1.98 (dq, J = 12.0, 7.0 Hz, 2H),
2.45 (td, J = 8.0, 7.0 Hz, 2H), 3.38 (dt, J = 15.5, 8.0 Hz, 1H), 3.52 (dt, J
= 15.5, 8.0 Hz, 1H), 3.73 (td, J = 8.5, 4.0 Hz, 1H), 3.77–3.81 (m, 2H),
4.13 (dd, J = 8.5, 2.0 Hz, 1H), 4.44 (dd, J = 7.5, 2.0 Hz, 1H), 4.98–5.08
(m, 2H), 5.51–5.65 (m, 2H), 5.73 (ddt, J = 12.0, 10.0, 7.0 Hz, 1H), 7.57–
7.99 ppm (m, 4H); 13C NMR (CDCl3, 100 MHz): d = ꢀ5.5, ꢀ5.4, 13.1,
18.4, 25.5, 25.9, 26.9, 35.3, 45.4, 60.3, 63.3, 79.2, 81.1, 109.5, 116.7, 120.8,
124.0, 130.6, 131.3, 133.2, 134.1, 135.0, 139.5, 148.4 ppm; IR (KBr): n˜ =
1546, 1372, 1178, 853, 747 cmꢀ1
C24H28N2O9S2: C 52.16, H 5.11, N 5.07; found: C 52.15, H 5.21, N 5.11.
;
elemental analysis calcd (%) for
(2S)-{(1’S,2’S)-1’,2’-Dihydroxy-3’-[(p-toluenesulfonyl)oxy]propyl}-N-(2-ni-
trobenzenesulfonyl)-3,4-dehydropiperidine (26): A solution of acetonide
25 (340 mg, 0.62 mmol) in a mixture of THF (15.0 mL) and HCl (3n,
10.0 mL) was heated at 508C for 5 h. The reaction mixture was concen-
trated, and the resultant aqueous layer was extracted with AcOEt. The
combined extract was washed with water, saturated aqueous NaHCO3,
and brine, and was dried over anhydrous Na2SO4. After concentration
under reduced pressure, purification of the resulting oil by silica gel chro-
matography (AcOEt/hexane 1:1) furnished the corresponding diol
(289 mg, 92%).
2933, 1547, 1373, 1171, 778 cmꢀ1
; elemental analysis calcd (%) for
C27H44N2O7SSi: C 57.01, H 7.80, N 4.93; found: C 56.92, H 7.77, N 5.12.
(2S)-(1’S,2’S)-3’-[(tert-Butyldimethylsilyl)oxy]-[1’,2’-(isopropylidenedi-
oxy)propyl]-N-(2-nitrobenzenesulfonyl)-3,4-dehydro-piperidine (23):
A
dry Schlenk flask was charged with 22 (211 mg, 0.37 mmol) and benzene
(19.0 mL) and the solution was degassed by three freeze-thaw cycles.
After the Schlenk flask had been cooled to ꢀ788C, benzylidenebis(tricy-
clohexylphosphine)dichlororuthenium (21 mg, 0.026 mmol) was placed
on the resulting solidified mixture. The Schlenk flask was evacuated and
then heated at 608C for 90 min. After cooling to room temperature, the
reaction mixture was concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography (AcOEt/hexane 1:10)
to afford cyclized lactam 23 (175 mg, 92%) as a colorless oil: [a]D26
ꢀ193.5 (c = 1.30, CHCl3); 1H NMR (CDCl3, 400 MHz): d = 0.08 (s,
6H), 0.90 (s, 9H), 1.38 (s, 3H), 1.40 (s, 3H), 1.85–2.01 (m, 2H), 3.41
(ddd, J = 15.0, 11.0, 5.5 Hz, 1H), 3.97 (dd, J = 15.0, 5.5 Hz, 1H), 4.04–
4.10 (m, 1H), 4.14 (dd, J = 7.0, 6.5 Hz, 1H), 4.47–4.52 (m, 1H), 5.79–
5.92 (m, 2H), 7.55–8.00 ppm (m, 4H); 13C NMR (CDCl3, 100 MHz): d =
ꢀ5.5, ꢀ5.4, 18.3, 23.1, 25.9, 27.1, 27.2, 40.1, 55.7, 63.0, 79.2, 79.7, 109.3,
124.0, 124.6, 126.6, 130.3, 131.5, 133.5, 134.2, 148.2 ppm; IR (KBr): n˜ =
A portion of the resulting diol (146 mg, 0.29 mmol) in dimethoxymethane
(25.0 mL) was stirred at room temperature for 1.5 h in the presence of
solid phosphorus pentoxide (ca. 20 mg). The reaction mixture was diluted
with Et2O and poured into water. The separated aqueous layer was ex-
tracted with AcOEt, and the combined organic extract was washed with
saturated aqueous NaHCO3 and brine, and dried over anhydrous
Na2SO4. After concentration under reduced pressure, the resulting resi-
due was purified by silica gel chromatography (AcOEt/hexane 1:2) to
give bis-methoxymethyl ether 26 (137 mg, 80%) as a white crystalline
solid: Mp 115–1188C; [a]D23 ꢀ152.1 (c = 1.02, CHCl3); 1H NMR (CDCl3,
400 MHz): d = 1.85–2.04 (m, 2H), 2.46 (s, 3H), 3.34 (s, 3H), 3.35 (s,
3H), 3.82 (dd, J = 6.0, 4.0 Hz, 1H), 4.23 (dd, J = 10.0, 6.0 Hz, 1H), 4.29
(dd, J = 10.0, 6.0 Hz, 1H), 4.62–4.73 (m, 5H), 5.73–5.79 (m, 1H), 5.79–
5.85 (m, 1H), 7.34–7.99 ppm (m, 8H); 13C NMR (CDCl3, 100 MHz): d =
21.6, 23.0, 39.8, 53.5, 55.9, 56.6, 68.6, 75.8, 80.1, 98.1, 98.5, 123.9, 124.3,
127.0, 128.0, 129.9, 130.4, 131.6, 132.7, 133.6, 133.6, 145.1, 148.1 ppm; IR
(KBr): n˜ = 1545, 1362, 1178, 747 cmꢀ1; elemental analysis calcd (%) for
C17H34O4Si: C 49.99, H 5.37, N 4.66; found: C 50.00, H 5.11, N 4.65.
2932, 1547, 1373, 1171, 747 cmꢀ1
; elemental analysis calcd (%) for
C23H36N2O7SSi: C 53.88, H 7.08, N 5.46; found: C 53.83, H 6.90, N 5.22.
(2S)-(1’S,2’S)-3’-Hydroxy-[1’,2’-(isopropylidenedioxy)-propyl]-N-(2-nitro-
benzenesulfonyl)-3,4-dehydro-piperidine (24): A solution of tetrabutyl-
ammonium fluoride (1m solution in THF, 360 mL, 0.36 mmol) was added
to a solution of silyl ether 23 (134 mg, 10.3 mmol) in CH3CN (5.0 mL).
The reaction mixture was stirred at room temperature for 6 h and was
then concentrated under reduced pressure. Purification of the resulting
residue by silica gel chromatography (AcOEt/hexane 1:1) afforded alco-
hol 24 (94 mg, 91%) as a colorless oil: [a]2D3 ꢀ301.2 (c = 0.94, CHCl3);
1H NMR (CDCl3, 400 MHz): d = 1.42 (s, 3H), 1.43 (s, 3H), 1.87–2.03
(m, 2H; H-2), 3.29–3.39 (m, 1H), 3.72 (ddd, J = 12.0, 8.0, 4.0 Hz, 1H),
3.88 (dt, J = 12.0, 4.0 Hz, 1H), 4.06 (t, J = 7.5 Hz, 1H), 4.19 (dt, J =
7.5, 3.5 Hz, 1H), 4.44–4.50 (m, 1H), 5.79–5.86 (m, 1H), 5.91 (dq, J =
10.5, 2.0 Hz, 1H), 7.57–8.02 ppm (m, 4H); 13C NMR (CDCl3, 100 MHz):
d = 22.8, 27.0, 27.1, 39.9, 55.8, 62.3, 78.5, 79.7, 109.5, 124.1, 124.9, 126.3,
130.4, 131.6, 133.7, 133.8, 148.1 ppm; IR (KBr): n˜ = 3447, 1545, 1373,
1168, 748 cmꢀ1; HRMS (FAB): found: 399.1232 [M+H]+; C17H23O7N2S
calcd 399.1226; elemental analysis calcd (%) for C17H22N2O7S: C 51.25, H
5.57, N 7.03; found: C 51.27, H 5.42, N 6.98.
(1S,2S,8aS)-1,2-Bis(methoxymethoxy)-1,2,3,5,6,8a-hexahydro-indolizine
(28): Thiophenol (16 mL, 0.16 mmol) was added to a suspension of 26
(32 mg, 0.053 mmol) and cesium carbonate (52 mg, 0.16 mmol) in aceto-
nitrile (8.0 mL). After being stirred at room temperature for 1.5 h, the re-
action mixture was filtered through a pad of Hyflo Super Cellꢃ , and the
filtrate was concentrated under reduced pressure. The resulting residue
was purified by silica gel chromatography (dichloromethane/methanol,
30:1) to afford cyclized product 28 (11 mg, 85%) as a colorless oil: [a]D26
ꢀ51.7 (c = 1.08, CHCl3); 1H NMR (CDCl3, 300 MHz): d = 1.90–2.04
(m, 1H), 2.24–2.42 (m, 1H), 2.69 (ddd, J = 12.0, 10.0, 5.0 Hz, 1H), 2.92–
3.04 (m, 3H), 3.08–3.16 (m, 1H), 3.38 (s, 3H), 3.40 (s, 3H), 3.84 (dd, J =
6.0, 3.0 Hz, 1H), 4.14 (ddd, J = 6.0, 4.5, 3.0 Hz, 1H), 4.64–4.80 ppm (m,
4H); 13C NMR (CDCl3, 75 MHz): d = 22.8, 46.7, 55.4, 55.5, 56.5, 64.3,
81.6, 86.8, 95.9, 96.1, 126.1, 126.5 ppm; IR (KBr): n˜
= 1152, 1106,
1043 cmꢀ1; HRMS (FAB): found: 244.1571 [M+H]+ C12H22NO4 calcd
244.1549.
(1S,2S,8aS)-1,2-Bis(methoxymethoxy)indolizidine (29):
A mixture of
alkene 28 (14 mg, 0.058 mmol) and platinum on activated carbon (6 mg)
in ethanol (6.0 mL) was vigorously stirred under hydrogen atmosphere
for 2 h. The mixture was filtered through a pad of Hyflo Super Cell, and
concentrated under reduced pressure. The residue was purified by silica
gel chromatography (dichloromethane/methanol 40:1) to afford indolizi-
dine 29 (12 mg, 85%) as a colorless oil: [a]2D4 ꢀ30.0 (c = 0.73, CHCl3)
(lit.[6e] [a]D20 ꢀ31, c = 1.52, CHCl3); 1H NMR (CDCl3, 300 MHz): d =
1.12–1.48 (m, 2H), 1.54–2.02 (m, 5H), 1.90–2.02 (m, 1H), 2.38–2.46 (dd,
J = 10.5, 5.5 Hz, 1H), 2.98–3.07 (m, 2H), 3.39 (s, 6H), 3.77 (dd, J = 8.0,
2.0 Hz, 1H), 4.01 (dd, J = 5.5, 2.0 Hz, 1H), 4.63–4.82 ppm (m, 4H); 13C
NMR (CDCl3, 75 MHz): d = 24.0, 24.7, 29.0, 53.3, 55.4, 55.5, 59.7, 68.8,
(2S)-{(1’S,2’S)-1’,2’-(Isopropylidenedioxy)-3’-[(p-toluenesulfonyl)oxy]-
propyl}-N-(2-nitrobenzenesulfonyl)-3,4-dehydropiperidine (25):
A so-
lution of alcohol 24 (175 mg, 0.44 mmol) and Et3N (1.1 mL, 7.92 mmol)
in CH2Cl2 (12.0 mL) was treated at 08C with p-toluenesulfonyl chloride
(755 mg, 3.96 mmol). After the mixture had been stirred at room temper-
ature for 4 h, N,N-dimethyl-1,3-propanediamine (550 mL, 4.4 mmol) was
added to quench the excess p-toluenesulfonyl chloride. The mixture was
diluted with ether and poured into water. The aqueous layer was extract-
ed with AcOEt. The combined organic extract was washed with aqueous
KHSO4 (1m), water, saturated aqueous NaHCO3, and brine, and dried
over anhydrous Na2SO4. Concentration under reduced pressure provided
a residue, which was purified by silica gel chromatography (AcOEt/
hexane 1:2) to furnish the tosylate 25 (221 mg, 91%) as a colorless oil:
[a]2D6 ꢀ172.6 (c = 1.33, CHCl3); 1H NMR (CDCl3, 400 MHz): d = 1.35
(s, 3H), 1.39 (s, 3H), 1.83–1.90 (m, 2H), 2.45 (s, 3H), 3.20–3.31 (m, 1H),
3.88–3.95 (m, 1H), 4.06 (t, J = 7.5 Hz, 1H), 4.19 (d, J = 3.5 Hz, 2H),
4.26 (td, J = 7.5, 3.5 Hz, 1H), 4.39–4.44 (m, 1H), 5.77–5.89 (m, 2H),
7.33–8.00 ppm (m, 8H); 13C NMR (CDCl3, 100 MHz): d = 21.6, 22.7,
26.8, 27.0, 39.9, 55.7, 69.0, 77.0, 78.2, 110.2, 124.1, 124.6, 126.6, 128.1,
129.9, 130.4, 131.7, 132.6, 133.6, 133.8, 145.0, 148.1 ppm; IR (KBr): n˜ =
79.6, 87.6, 95.3, 95.9 ppm; IR (KBr): n˜ = 2936, 1152, 1107, 1041 cmꢀ1
HRMS (FAB): found: 246.1728 [M+H]+; C12H24NO4 calcd 246.1705.
;
Lentiginosine (1): A solution of indolizidine 29 (19 mg, 0.077 mmol) was
dissolved in a mixture of methanol (6.0 mL) and HCl (3n, 2.0 mL). After
stirring at 558C for 5 h, the solution was concentrated under reduced
pressure. The resulting hydrochloride was purified by silica gel chroma-
tography (CH2Cl2/CH3OH/28% aq. NH3 85:14:1) to afford the residue,
which was passed through an ion-exchange column of IRA-410 (H2O) to
furnish lentiginosine (1; 10 mg, 82%) as a white solid: [a]2D7 +1.06 (c =
0.47, MeOH) (lit.[6e] [a]D20 +2.8, c = 0.28, MeOH) (lit.[6f] [a]2D5 +3.2, c =
Chem. Eur. J. 2005, 11, 1949 – 1957
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1955

Y. Ichikawa et al.
0.27, MeOH) (lit.[6l] [a]D24 +3.1, c = 0.31, MeOH); 1H NMR (CDCl3,
300 MHz): d = 1.14–1.34 (m, 2H), 1.38–1.69 (m, 2H), 1.74–1.97 (m, 2H),
1.88–1.97 (m, 2H), 2.04 (td, J = 11.0, 3.0 Hz, 1H), 2.61 (dd, J = 11.0,
7.5 Hz, 1H), 2.82 (dd, J = 11.0, 2.0 Hz, 1H), 2.93 (brd, J = 11.0 Hz,
1H), 3.64 (dd, J = 9.0, 4.0 Hz, 1H), 4.06 ppm (ddd, J = 8.0, 4.0, 2.0 Hz,
1H); 13C NMR (CDCl3, 75 MHz): d = 22.8, 23.8, 27.4, 52.4, 60.1, 68.3,
(AcOEt/hexane 1:10) to afford methyl ester 32 (39 mg, 97%) as a color-
less oil: [a]2D7 +0.26 (c = 1.14, CHCl3); 1H NMR (C6D6, 400 MHz): d =
0.06 (s, 3H), 0.07 (s, 3H), 0.97 (s, 9H), 1.25 (s, 3H), 1.30 (s, 3H), 1.41 (s,
9H), 3.21 (s, 3H), 3.71 (dd, J = 11.0, 5.5 Hz, 1H), 3.80 (dd, J = 11.0,
4.0 Hz, 1H), 4.15 (ddd, J = 8.0, 5.5, 4.0 Hz, 1H), 4.66 (dd, J = 8.0,
1.0 Hz, 1H), 4.86 (dd, J = 9.5, 1.0 Hz, 1H), 5.10 ppm (brd, J = 9.5 Hz,
1H); 13C NMR (C6D6, 100 MHz): d = ꢀ5.4, ꢀ5.4, 18.5, 26.1, 26.9, 27.2,
28.3, 52.0, 54.1, 63.3, 77.5, 79.0, 79.8, 109.6, 156.2, 171.0 ppm; IR (KBr): n˜
75.5, 82.8 ppm; IR (KBr): n˜
158.1210 [M+H]+; C8H15N1O2 calcd 158.1181.
= ; HRMS (FAB): found:
3309 cmꢀ1
=
3448, 2933, 1757, 1720, 1253, 1165 cmꢀ1
434.2525 [M+H]+; C20H40NO7Si calcd 434.2574.
; HRMS (FAB): found:
(3E,5R,6S,7S)-5-[(tert-Butoxycarbonyl)amino]-8-[(tert-butyldimethyl-
silyl)oxy]-6,7-(isopropylidenedioxy)-oct-3-ene (30): Zinc powder (863 mg,
13.2 mmol) was added at room temperature to a solution of allyl carba-
mate 18 (392 mg, 0.78 mmol) and AcOH (310 mL, 5.43 mmol) in THF
(15.0 mL). After being stirred vigorously for 6 h, the suspension was di-
luted with AcOEt and was then filtered through a pad of Hyflo Super
Cell. The filtrate was concentrated under reduced pressure to afford the
crude allyl amine, which was dissolved in THF (20.0 mL). The solution
was treated with Et3N (140 mL, 1.01 mmol) and Boc2O (230 mL,
1.01 mmol) at room temperature. After being stirred at room tempera-
ture for one day, the solution was concentrated under reduced pressure,
and the resulting residue was purified by silica gel chromatography
(AcOEt/hexane 1:8) to afford Boc-carbamate 30 (293 mg, 88%) as a col-
Methyl 2-N-[(tert-butoxycarbonyl)amino]-2-deoxy-3,4-O-isopropylidene-
l-xylonate (33): A solution of methyl ester 32 (17 mg, 0.039 mmol), dis-
solved in acetic acid (0.90 mL), THF (0.30 mL), and H2O (0.30 mL), was
stirred at room temperature for 2 days. THF was removed under reduced
pressure, and the aqueous layer was extracted with AcOEt. The com-
bined organic extract was washed with saturated aqueous NaHCO3 and
brine, and dried over anhydrous Na2SO4. Concentration under reduced
pressure, followed by purification by silica gel chromatography (AcOEt/
hexane 1:1), furnished alcohol 33 (11 mg, 88%) as a colorless oil: [a]D27
+
14.9 (c = 0.94, CHCl3); 1H NMR (CDCl3, 400 MHz): d = 1.40 (s, 3H),
1.41 (s, 3H), 1.46 (s, 9H), 2.34 (br, 1H), 3.91 (dt, J = 8.0, 4.0 Hz, 1H),
4.37 (dd, J = 8.5, 1.5 Hz, 1H), 4.46 (dd, J = 9.0, 1.5 Hz, 1H), 5.41 ppm
(brd, J = 9.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz): d = 26.8, 27.0,
28.3, 52.8, 53.1, 61.5, 76.9, 77.8, 80.5, 109.6, 156.1, 170.6 ppm; IR (KBr): n˜
= 3447, 2985, 1751, 1717, 1508, 1370, 1250, 1165 cmꢀ1; HRMS (FAB):
found: 320.1688 [M+H]+; C14H26NO7 calcd 320.1709.
1
orless oil: [a]2D6 +1.3 (c = 1.03, CHCl3); H NMR (CDCl3, 400 MHz): d
= 0.09 (s, 6H), 0.91 (s, 9H), 0.99 (t, J = 7.5 Hz, 3H), 1.37 (s, 3H), 1.41
(s, 3H), 1.44 (s, 9H), 2.02–2.12 (m, 2H), 3.68–3.76 (m, 1H), 3.77–3.87 (m,
2H), 3.95–4.02 (m, 1H), 4.29 (brs, 1H), 5.18 (brs, 1H), 5.45 (dtd, J =
15.5, 6.0, 1.0 Hz, 1H), 5.68 ppm (dtd, J = 15.5, 7.0, 0.5 Hz, 1H); 13C
NMR (CDCl3, 100 MHz): d = ꢀ5.5, ꢀ5.4, 13.4, 18.4, 25.3, 25.4, 26.0,
26.9, 27.0, 28.4, 63.3, 77.5, 79.3, 80.7, 108.9, 126.5, 134.0, 155.5 ppm; IR
(KBr): n˜ = 2932, 1718, 1368, 1253, 1170 cmꢀ1; elemental analysis calcd
(%) for C17H34O4Si: C 61.50, H 10.09, N 3.26; found: C 61.51, H 10.28, N
3.11.
Methyl 5-O-(aminocarbonyl)-2-[N-tert-butoxycarbonyl]amino]-2-deoxy-
3,4-O-isopropylidene-l-xylonate (2): Trichloroacetyl isocyanate (12 mL,
0.10 mmol) was added at 08C to
a solution of alcohol 33 (16 mg,
0.050 mmol) in CH2Cl2 (3.0 mL). After the mixture had been stirred at
08C for 5 min, Al2O3 (400 mg) was added. The solvent was removed
under reduced pressure, and the resulting solid was allowed to stand for
2 h and was then eluted with AcOEt. The eluent was concentrated and
purified by silica gel chromatography (AcOEt/hexane, 2:1) to afford car-
bamate 2 (15 mg, 86%) as a colorless oil: [a]2D3 ꢀ2.2 (c = 0.54, CH2Cl2)
(lit.[9] [a]2D3 ꢀ2.8, c = 0.84, CH2Cl2); 1H NMR (CDCl3, 400 MHz): d =
1.39 (s, 3H), 1.42 (s, 3H), 1.46 (s, 9H), 3.80 (s, 3H), 4.02 (dt, J = 8.5,
5.0 Hz, 1H), 4.24–4.27 (m, 2H), 4.29 (dd, J = 8.5, 1.5 Hz, 1H), 4.51 (dd,
J = 9.5, 1.5 Hz, 1H), 4.87 (brs, 2H), 5.30 ppm (brd, J = 9.5 Hz, 1H);
13C NMR (CDCl3, 100 MHz): d = 26.8, 26.8, 28.3, 52.8, 53.1, 64.1, 74.9,
78.3, 80.5, 110.1, 155.9, 156.1, 170.6 ppm; IR (KBr): n˜ = 3448, 3365, 1719,
1370, 1251, 1166, 1071 cmꢀ1. HRMS (FAB): found: 363.1721 [M+H]+;
C15H27N2O8 calcd 363.1767.
2-N-[(tert-Butoxycarbonyl)amino]-5-O-(tert-butyldimethylsilyl)-2-deoxy-
3,4-O-isopropylidene-l-xylonic acid (31): A solution of the alkene 30
(227 mg, 0.53 mmol) in methanol (15.0 mL) was cooled to ꢀ788C. Ozone
was passed through the solution until starting material had been con-
sumed (TLC analysis). The resulting blue solution was purged with
oxygen for 10 min, and dimethyl sulfide (270 mL, 3.70 mmol) was then
added. After the mixture had been stirred at ꢀ788C for 10 min, saturated
aqueous NaHCO3 was added. The separated aqueous layer was extracted
with CH2Cl2, and the combined organic extracts were washed with brine,
dried over anhydrous Na2SO4, and then concentrated under reduced
pressure.
The resulting residue, dissolved in a mixture of tBuOH (20.0 mL) and
H2O (4.0 mL), was treated with Na2HPO4 (375 mg, 2.64 mmol), 2-methyl-
but-2-ene (1 drop), and NaClO2 (143 mg, 1.58 mmol). After stirring at
room temperature for 70 min, the mixture was poured into aqueous
KHSO4 (1m). The aqueous layer was extracted with CH2Cl2, and the
combined organic extract was washed with brine and dried over anhy-
drous Na2SO4. Concentration under reduced pressure, followed by purifi-
cation by silica gel chromatography (AcOEt/hexane/acetic acid 16:83:1),
afforded carboxylic acid 31 (189 mg, 85%), which was further purified by
recrystallization to yield an analytically pure sample as a white crystalline
solid: m.p. 133–1358C; [a]2D7 +4.1 (c = 1.04, CHCl3); 1H NMR (C6D6,
400 MHz): d = 0.06 (s, 3H), 0.07 (s, 3H), 0.97 (s, 9H), 1.25 (s, 3H), 1.27
(s, 3H), 1.39 (s, 9H), 3.70 (dd, J = 10.5, 5.5 Hz, 1H), 3.79 (dd, J = 10.5,
4.0 Hz, 1H), 4.07–4.14 (m, 1H), 10.40 ppm (brs, 1H); 13C NMR (C6D6,
100 MHz): d = ꢀ5.4, 18.5, 26.1, 26.9, 27.0, 28.3, 53.9, 63.2, 77.6, 78.7,
80.1, 109.7, 156.4, 175.4 ppm; IR (KBr): n˜ = 3399, 2932, 1749, 1718, 1165,
1090 cmꢀ1; elemental analysis calcd (%) for C17H34O4Si: C 54.39, H 8.89,
N 3.34; found: C 54.42, H 8.65, N 3.12.
Acknowledgements
This research was financially supported from MEXT by a Grant-In-Aid
for Specially Promoted Research, (16002007).
[1] Y. Ichikawa, Synlett 1991, 238.
[2] Y. Ichikawa, T. Ito, T. Nishiyama, M. Isobe, Synlett 2003, 1034.
[3] Y. Ichikawa, K. Tsuboi, M. Isobe, J. Chem. Soc. Perkin Trans. 1
1994, 2791.
[4] Y. Ichikawa, M. Osada, I. Ohtani, M. Isobe, J. Chem. Soc. Perkin
Trans. 1 1997, 1449.
[5] For a review of matched-mismatched problems, see: S. Masamune,
W. Choy, J. S. Peterson, L. R. Sita, Angew. Chem. 1985, 97, 1;
Angew. Chem. Int. Ed. Engl. 1985, 24, 1.
Methyl 2-N-[(tert-butoxycarbonyl)amino]-5-O-(tert-butyldimethylsilyl)-2-
deoxy-3,4-O-isopropylidene-l-xylonate (32):
A solution of carboxylic
[6] a) Isolation: I. Pastuszak, R. J. Molyneux, L. F. James, A. D. Elbein,
Biochemistry 1990, 29, 188; b) For synthetic works, see: H. Yoda, H.
Kitayama, T. Katagiri, K. Takabe, Tetrahedron: Asymmetry 1993, 4,
1455; c) M. K. Gurjar, L. Ghosh, M. Syamala, V. Jayasree, Tetrahe-
dron Lett. 1994, 35, 8871; d) S. Nukui, M. Sodeoka, H. Sasai, M. Shi-
basaki, J. Org. Chem. 1995, 60, 398; e) R. Giovannini, E. Marcanto-
ni, M. Petrini, J. Org. Chem. 1995, 60, 5706; f) A. Brandi, S. Cicchi,
acid 31 (39 mg, 0.093 mol), dissolved in Et2O (3.0 mL) and cooled to
08C, was treated with an ethereal solution of diazomethane until a
yellow-colored solution persisted. The excess diazomethane was
quenched by dropwise addition of acetic acid until the color dissipated.
The resulting reaction mixture was concentrated under reduced pressure
to give a residue, which was purified by silica gel chromatography
1956
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 1949 – 1957

Stereoselective Allyl Amine Synthesis
FULL PAPER
F. M. Cordero, R. Frignoli, A. Goti, S. Picasso, P. Vogel, J. Org.
Chem. 1995, 60, 6806; g) A. Goti, F. Cardona, A. Brandi, Synlett
1996, 761; h) H. Yoda, M. Kawauchi, K. Takabe, Synlett 1998, 137;
i) A. E. McCaig, K. P. Meldrum, R. H. Wightman, Tetrahedron 1998,
54, 9429; j) D.-C. Ha, C.-S. Yun, Y. Lee, J. Org. Chem. 2000, 65, 621;
k) H. Yoda, H. Katoh, Y. Ujihara, K. Takabe, Tetrahedron Lett.
2001, 42, 2509; l) M. O. Rasmussen, P. Delair, A. E. Greene, J. Org.
Chem. 2001, 66, 5438; m) S. H. Lim, S. Ma, P. Beak, J. Org. Chem.
2001, 66, 9056; n) C. F. Klitzke, R. A. Pilli, Tetrahedron Lett. 2001,
42, 5605; o) J. Rabiczko, Z. Urbanczyk-Lipkowska, M. Chmielewski,
Tetrahedron 2002, 58, 1433; p) K. L. Chandra, M. Chandrasekhar,
V. K. Singh, J. Org. Chem. 2002, 67, 4630; q) Z.-X. Feng, W.-S.
Zhou, Tetrahedron Lett. 2003, 44, 497; r) T. Ayad, Y. Genisson, M.
Baltas, L. Gorrichon, Chem. Commun. 2003, 582.
[13] I. Ohtani, K. Kusumi, Y. Kashman, H. Kakisawa, J. Am. Chem. Soc.
1991, 113, 4092.
[14] An inseparable mixture of allyl alcohols 10 and 11 (93:7 ratio, only
major isomer is depicted) was employed as starting material. The re-
sulting rearranged product was also a mixture of two diastereomers
16 and 18 (ca. 93:7, confirmed by 1H NMR), which is consistent
with the [1,3]-chirality transfer of the allyl cyanate-to-isocyanate re-
arrangement.
[15] T. Kusumi, I. Ohtani, T. Fukushima, H. Kakisawa, Tetrahedron Lett.
1991, 32, 2939.
[16] Although allyl cyanates such as A (Figure 7) have been considered
to be possible intermediates in the reaction, there is also some ex-
perimental evidence of their involvement. See: a) K. Banert, Angew.
Chem. 1992, 104, 865; Angew. Chem. Int. Ed. Engl. 1992, 31, 866;
b) K. Banert, A. Melzer, Tetrahedron Lett. 2001, 42, 6133.
[17] a) P. Schwab, M. B. France, J. W. Ziller, R. H. Grubbs, Angew.
Chem. 1995, 107, 2179; Angew. Chem. Int. Ed. Engl. 1995, 34, 2039;
b) R. H. Grubbs, S. Chang, Tetrahedron 1988, 44, 4413.
[18] T. Fukuyama, C-K. Jow, M. Cheung, Tetrahedron Lett. 1995, 36,
6373.
[19] The nosyl group appeared to enhance the cyclization reaction
through a buttressing effect. See: T. Kan, A. Fujiwara, H. Kobaya-
shi, T. Fukuyama, Tetrahedron 2002, 58, 6267.
[20] For the inherent ring strain imposed by the trans-acetonide group,
only the substitution product i was isolated by deprotection of the
o-nosyl amide in 25.
[7] a) Isolation : K. Isono, K. Asahi, S. Suzuki, J. Am. Chem. Soc. 1969,
91, 7499; b) For synthetic works, see: A. K. Saksena, R. G. Lovey,
V. M. Girijavallabhan, A. K. Ganguly, J. Org. Chem. 1986, 51, 5024;
c) M. Hirama, H. Hioki, S. Ito, Tetrahedron Lett. 1988, 29, 3125;
d) P. Garner, J. M. Park, J. Org. Chem. 1988, 53, 2979; e) A. Dureult,
F. Carreaux, J.-C. Depezay, Tetrahedron Lett. 1989, 30, 4527; f) M.
Paz, F. Sardina, J. Org. Chem. 1993, 58, 6990; g) A. Dondoni, S.
Franco, F. L. Merchan, P. Merino, T. Tejero, Tetrahedron Lett. 1993,
34, 5479; h) J. A. Marshall, B. M. Seletsky, P. S. Coan, J. Org. Chem.
1994, 59, 5139; i) F. Matsura, Y. Hamada, T. Shioiri, Tetrahedron
Lett. 1994, 35, 733; j) R. F. Jackson, N. J. Palmer, M. J. Wyther, W.
Clegg, M. Elsegood, J. Org. Chem. 1995, 60, 6431; k) S. H. Kang, H.
Choi, Chem. Commun. 1996, 1521; l) G. Veeresa, A. Datta, Tetrahe-
dron Lett. 1998, 39, 119; m) I. Savage, E. J. Thomas, P. D. Wilson, J.
Chem. Soc. Perkin Trans. 1 1999, 3291; n) F. A. Davis, K. R. Prasad,
P. J. Carroll, J. Org. Chem. 2002, 67, 7802; o) A. Tarrade, P. Dauban,
R. H. Dodd, J. Org. Chem. 2002, 67, 9521.
[8] K. Isono, J. Antibiot. 1988, 41, 1711.
[9] K. A. Ghosh, Y. Wang, J. Org. Chem. 1999, 64, 2789.
[10] H. Iida, N. Yamazaki, C. Kibayashi, J. Org. Chem. 1987, 52, 3337.
[11] K. Soai, A. Ookawa, T. Kaba, K. Ogawa, J. Am. Chem. Soc. 1987,
109, 7111.
[12] Aldehyde 9 was prepared in 90% yield by o-iodoxybenzoic acid
(IBX) oxidation of the allyl alcohol 7. For the IBX oxidation, see:
a) E. J. Corey, A. Palani, Tetrahedron Lett. 1995, 36, 3485; b) M. Fri-
gerio, M. Santagostino, S. Sputore, G. Palmisano, J. Org. Chem.
1995, 60, 7272.
[21] J. Yoshimura, M. Yamamura, T. Suzuki, H. Hashimoto, Chem. Lett.
1983, 1011.
[22] P. Kocovsky, Tetrahedron Lett. 1986, 27, 5521.
Received: August 12, 2004
Published online: January 25, 2005
Chem. Eur. J. 2005, 11, 1949 – 1957
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1957